Engineering Inducible Cell Fate Transitions by Harnessing Epigenetic Silencing

During development, cell-cell communication induces a series of cell fate transitions that are maintained by epigenetic gene regulation. Here, we harness endogenous epigenetic silencing machinery to develop synthetic circuits that induce stable gene expression changes. Using synthetic Notch receptors that control the chromatin regulators KRAB and Dnmt3L, we developed input-controlled switches capable of inducing self-sustaining silencing of target loci. We used these modules to construct circuits in which combinatorial inputs specifically direct a choice among multiple alternative cell fates. These epigenetic silencing switches can also be inverted to yield input-induced sustained activation of a target gene. We demonstrate that this epigenetic memory switch can be used to drive morphological fate changes, in response to transient cell signals, that remain stable over many cell divisions, as is observed in development. These synthetic epigenetic circuits represent an important step towards engineering cell populations capable of coordinated multi-cell fate decisions.